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Metastatic progression is associated with dynamic changes in the local microenvironment.

Nicole M Aiello1, David L Bajor1, Robert J Norgard1

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Metastatic pancreatic ductal adenocarcinoma (PDAC) lesions change with size. Adjuvant chemotherapy effectively targets these micrometastases, improving survival.

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Area of Science:

  • Oncology
  • Cancer Biology
  • Translational Research

Background:

  • Metastasis is a leading cause of cancer mortality.
  • The behavior and chemosensitivity of metastatic lesions, particularly in pancreatic ductal adenocarcinoma (PDAC), are not fully understood.
  • Factors like metastatic lesion size and microenvironment influence treatment efficacy.

Purpose of the Study:

  • To investigate the natural history and evolution of metastatic lesions in an autochthonous pancreatic ductal adenocarcinoma (PDAC) model.
  • To determine how metastatic lesion characteristics change with size.
  • To evaluate the efficacy of adjuvant chemotherapy against micrometastatic lesions.

Main Methods:

  • Utilized an autochthonous model of pancreatic ductal adenocarcinoma (PDAC).
  • Employed lineage tracing to track the evolution of disseminated cancer cells and their microenvironment.
  • Assessed the impact of gemcitabine and nab-paclitaxel treatment on metastatic lesions.

Main Results:

  • Metastatic lesions exhibited a shift in histology from mesenchymal to epithelial with increasing size.
  • Lesions became hypovascular and developed a desmoplastic stroma, resembling primary tumors.
  • Gemcitabine and nab-paclitaxel treatment reduced metastasis burden by inducing cell death across all lesion sizes.
  • The study challenges the notion that PDAC stroma is a critical barrier to chemotherapy drug delivery.

Conclusions:

  • Metastatic lesion progression involves dynamic changes in histology, vascularity, and stroma.
  • Adjuvant chemotherapy demonstrates significant efficacy against micrometastatic PDAC.
  • Chemotherapy provides a survival benefit by directly targeting early-stage metastatic disease.